Part of our assignment in which we have to make a paperwork and presentation of a few sub-topics (hepatotoxicity, renal toxicity, neurotoxicity, skeletal-muscle-toxicity) under the topic of Drug-induced Toxicity. Slide can be found in: http://www.slideshare.net/annisahayatunnufus/druginduced-toxicity-liver-kidney-nervous-system-muscle Students of Bachelor of Pharmacy Management & Science University

1. SCHOOL OF PHARMACY
Subject: PRINCIPLES OF MEDICAL PHARMACOLOGY
Subject code: SPH1102
Assignment #2: DRUG TOXICITY
GROUP 4: C) ORGAN & TISSUE TOXICITY
Prepared by:
NAME ID
1. PAVITRA A/P KRISHNAN 012014052393
2. ESHWARI A/P GUNASEGARAN 012014052405
3. ANNISA HAYATUNNUFUS 012014052438
4. DURGA DEVI A/P RAGGU 012014110838
5. VARISHAPRIYAA A/P CHANDRA
SEKARAN
012014052274
6. CHRISTINE SHALIN A/P SELVARAJ 012014052277
7.HONG TSHUN KUAN 012014110766
8. MUHAMMAD REZA ALFAATHIANSYAH 012014110827
9. MUHAMMAD HAIDIR BIN MOKHTAR 012014110769
10. YEOH CHUN SIONG 012014110822
Lecturer’s Name : MISS DEBRA DOROTEA
Date of submission : Wednesday, 27th June 2015

2. 2
RUBRIC
I. CONTENT............................................................................................................................ 3
1. Drug-induced Hepatotoxicity................................................................................ 3
A. Types of Liver Injury...................................................................................... 3
B. Risk Factors.................................................................................................... 4
C. Mechanism...................................................................................................... 4
D. Examples of Hepatoxicants.......................................................................... 5
E. Metabolic Activation of Hepatoxicants........................................................ 5
F. Prevention ....................................................................................................... 5
2. Drug-induced Renal Toxicity................................................................................ 6
A. Pathogenic Mechanisms............................................................................... 6
B. Drugs That Cause Nephrotoxicity ............................................................... 7
C. Symptoms of Nephrotoxicity........................................................................ 9
D. Treatment of Nephrotoxicity.......................................................................10
E. Prevention of Nephrotoxicity ......................................................................10
3. Drug-induced Neurotoxicity................................................................................11
A. Vinca Alkaloids-induced Neurotoxicity......................................................11
B. Taxanes-induced Neurotoxicity .................................................................13
C. Platinum Compound-induced Neurotoxicity............................................14
4. Drug-induced Skeletal Muscle Toxicity ............................................................16
A. Disorders.......................................................................................................16
B. Physiologic Mechanisms of Rhabdomyolisis...........................................17
C. Drug-induced Rhabdomyolisis Effects on Skeletal Muscle...................18
D. Examples of Drugs That Causes Rhabdomyolisis .................................19
E. Rhabdomyolisis Clinical Presentation ......................................................22
F. Rhabdomyolisis Treatment.........................................................................22
II. REFERENCES.................................................................................................................23

3. 3
I. CONTENT
1. DRUG-INDUCED HEPATOTOXICITY
The basic structure of liver consists of rows of hepatic cells (hepatocytes and
parencymal cells) perforated by specialized blood capillaries called sinusoids. The liver
plays a major role in storage, metabolizing and biosynthesis drugs and other chemicals
from the body and is susceptible to toxicity from these agents. Many drugs taken in
overdose cause hepatotoxic injury and some cause damage even when used in normal
therapeutic doses. Herbal agents, illicit drugs, and environmental chemicals can cause
hepatotoxicity. Hepatotoxicity is the main reason for postmarketing drug withdrawal. The
annual incidence of drug-induced hepatotoxicity ranges between 1.27 and 40.6 cases per
100,000 persons. Worldwide, the overall frequency of drug-induced liver diseases as a
percentage of all drug reactions is 3% to 9%. (JAMES E. TISDALE, DOUGLAS A.
MILLER, 2010)
A. Types of liver injury
The types of injury to the liver depend on the type of toxic agent, severity of
intoxification, and the type of exposure, whether acute or chronic.
a) Fatty liver:
Fatty liver refers to abnormal accumulation of fat in hepatocytes. Lipid
accumulation is related to disturbances in either the synthesis or secretion of
lipoproteins. Triglycerides are secreted from the liver as a very low density
lipoprotein (VLDL). This process can be disrupted when interference with transfer
of VLDL across cell membrane, decreased synthesis of phospholipids or impaired
conjugation of triglyceride with lipoprotein.
b) Necrosis:
Cell necrosis is a degenerative process leading to cell death. Necrosis,
usually an acute injury, may be localized and affect only few hepatocytes (focal
necrosis) or maybe involve the entire lobe (massive necrosis). The biochemical
events that contribute this condition are binding of reactive metabolites to proteins
and unsaturated lipids disturbance of cellular Ca+2 homeostasis, interference with
metabolic pathways, shifts in Na+ and K+ balance, and inhibition of protein
synthesis.
c) Apoptosis:
Apoptosis is a controlled form of cell death that serves as a regulation point
for biologic processes. Although apoptosis is a normal physiological process, it
can also be induced by a number of exogenous factors, such as xenobiotic
chemicals, oxidative stress, anoxia and radiation. Toxicants, however, do not
always act in a clear-cut fashion, and some toxicants can induce both apoptosis
and necrosis either concurrently or sequentially.

4. 4
d) Cholestasis:
Cholestasis is the suppression of bile flow, and may have either intrahepatic
or extrahepatic causes. Inflammation or blockage of the bile ducts results in
retention of bile salts as well as bilirubin accumulation, an event that lead to
jaundice. Cholestasis is usually a drug induced and difficult to produce in
experimental animals.
B. Risk Factors
 Genetic predisposition
 Sex
 Age
 Alcohol consumption
 Magnetic of a single dose or
cumulative dose
 Chronic viral infections (HIV)
 Pharmacokinetics or pharmacodynamic
interactions
 Illicit drug use (cocaine) and toxic mushrooms
 Food exposures or household or occupational
exposure to chemical agents
(JAMES E. TISDALE, DOUGLAS A. MILLER,
2010)
C. Mechanisms of hepatoxicity:
Cell injury can be initiated by a number of mechanisms, such as inhibition of
enzymes, depletion of cofactors or metabolites or depletion of energy (ATP) stores,
interaction with receptors and alteration of cell membranes. In recent years attention
has focused on biotransformation of chemicals to highly reactive metabolites that
initiate cellular toxicity. Many compounds, including clinically useful drugs, can cause
cellular damage through metabolic activation of the chemical to highly reactive
compounds, such as free radicals, carbenes, and nitrenes.
These reactive metabolites can bind covalently to cellular macromolecules
such as nucleic acids, proteins, cofactors, lipids, and polysaccharides, thereby
changing their biologic properties. The liver is particularly vulnerable to toxicity
produced by reactive metabolites because it is the major site of xenobiotic
metabolism. Most activation reactions are catalyzed by the cytochrome P450
enzymes, and agents that induce these enzymes, such as Phenobarbital and 3-
methylcholantherene, often increases toxicity. Conversely, inhibitors of cytochrome
P450, such as SKF25A and piperonylbutoxide, frequently decrease toxicity.
Mechanisms such as conjugation of reactive chemical with glutathione are
protective mechanisms that exist within the cell for the rapid removal and inactivation
of many potentially toxic compounds. Because of these interactions, cellular toxicity is
a function of the balance between the rate of formation of reactive metabolites and
the rate of their removal.

5. 5
D. Examples of hepatotixicants
 Carbon tetrachloride
 Ethanol
 Bromobenzene
 Acetaminophen
E. Metabolic activation of hepatotixicants
Liver toxicity caused by Bromobenzene, acetaminophen, and other
compounds have led to some important observations concerning tissue damage.
 Toxicity may be correlated with the formation of a minor but highly reactive
intermediate.
 A threshold tissue concentration of the reactive metabolite must be attained
before tissue injury occurs.
 Endogenous substances, such as glutathione, play an essential role in protecting
the cell from injury by removing chemically reactive intermediates and by keeping
the sulfhydrl groups of proteins in the reduced state.
 Pathways such as those catalyzed by glutathione transferase and epoxide
hydrolases play an important role in protecting the cell.
 Agents that selectively induce or inhibits the xenobiotic metabolizing enzymes
may alter the toxicity of xenobiotic chemicals. (HODGSON, 2004)
F. Prevention:
Recognition and rapid discontinuation of the agent is the best preventive
measure. Patient with risk factors should not receive hepatotoxic agents if and when
alternative agents are available. Many manufactures of drugs known to cause hepatic
injury provide guidelines for monitoring liver enzymes while patients are receiving the
potential hepatotoxin (isoniazide, etretinate, synthetic retinoids, ketoconazole,
methotrexate, pemoline, tacrine). Monthly monitoring liver associated biochemistry
may be cost-effective for drugs that produces serious liver dysfunction in 1% to 2% of
exposures, but not for drugs that are less frequently associated with this drug-induced
hepatotoxicity. (JAMES E. TISDALE, DOUGLAS A. MILLER, 2010).

6. 6
2. DRUG-INDUCED RENAL TOXICITY
Drugs are a common source of acute kidney injury. Drugs shown to cause
renal toxicity exert their toxic effects by one or more common pathogenic
mechanisms. Drug-induced renal toxicity tends to be more common among certain
patients and in specific clinical situation. Some patient-related risk factors for drug-
induced renal toxicity are age older than 60 years, underlying renal insufficiency (e.g.,
glomerular filtration rate of less than 60 mL per minute per 1.73 m2), volume
depletion, diabetes and heart failure.
A. Pathogenic mechanisms
Most drugs found to cause renal toxicity exert toxic effects by one or more
common pathogenic mechanisms. These include tubular cell toxicity, inflammation
and thrombotic microangiopathy.
I. Tubular cell toxicity
Renal tubular cells, in particular proximal tubule cells, are vulnerable to
the toxic effects of drugs because their role in concentrating and reabsorbing
glomerular filtrate exposes them to high levels of circulating toxins. Drugs that
cause tubular cell toxicity do so by impairing mitochondrial function, interfering
with tubular transport, increasing oxidative stress, or forming free radicals.
Drugs associated with this pathogenic mechanism of injury include
aminoglycosides, antiretrovirals (adefovir [Hepsera], cidofovir [Vistide], tenofovir
[Viread]), cisplatin (Platinol), contrast dye, foscarnet (Foscavir), and zoledronate
(Zometa).
II. Inflammation
Drugs can cause inflammatory changes in the glomerulus, renal tubular
cells, and the surrounding interstitium, leading to fibrosis and renal scarring.
Glomerulonephritis is an inflammatory condition caused primarily by immune
mechanisms and is often associated with proteinuria in the nephrotic range.
Medications such as gold therapy, hydralazine (Apresoline; brand not available
in the United States), interferon-alfa (Intron A), lithium, NSAIDs, propylthiouracil,
and pamidronate (Aredia; in high doses or prolonged courses) have been
reported as causative agents.
III. Thrombotic microangiopathy
Organ damage is caused by platelet thrombi in the microcirculation, as in
thrombotic thrombocytopenic purpura. Mechanisms of renal injury secondary to
drug-induced thrombotic microangiopathy include an immune-mediated reaction

7. 7
or direct endothelial toxicity. Drugs most often associated with this pathogenic
mechanism of nephrotoxicity include antiplatelet agents (e.g.,
clopidogrel[Plavix], ticlopidine [Ticlid]), cyclosporine, mitomycin-C (Mutamycin),
and quinine (Qualaquin).
B. Drugs that cause nephrotoxicity
Aminoglycoside antibiotics cover Gram-negative infections. They are
prototype drugs having nephrotoxicity as major side effects. It remains relatively
common cause of acute deterioration in renal function. Renal toxicity is caused by
proximal tubular injury that leads that cause cell necrosis. Nephrotoxic risk increases
with Na+ and K+ depleted state, renal ischemia, increasing age, liver disease,
diuretics, concomitant use of nephrotoxic agents and with duration of therapy
reaching, 50% when given for 14 days or more.
Relative toxicity: neomycin > gentamycin > tobramycin
>netilmycin>amikacin> streptomycin
Acute lithium-induced renal injury may present as early as 8 weeks after
treatment initiation and cause a reduced urinary concentrating capacity. When serum
concentrations are high, for example, 1.2 mmol/L), urine output increases and
glomerular filtration rate decreases mildly. Acute renal failure has been reported with
lithium intoxication, but the mechanism is uncertain and it may be due to factors such
as volume depletion, direct nephrotoxicity or a combination of both. Nephrogenic
diabetes insipidus is the most common adverse effect of lithium therapy and may
occur up to 40% of patients.
Over-the-counter availability of these Non-steroidal anti-inflammatory drugs
(NSAIDs) puts a large population at risk. Higher than usual dose, volume depletion,
congestive heart failure, nephrotic syndrome, cirrhosis particularly with ascites, pre-
Commonly-used drugs which can affect renal function
Diuretics
Beta blockers
Vasodilators
Non-steroidal anti-inflammatory drugs
ACE inhibitors
Aminoglycosides
Radio contrast media
Compound analgesics
Antiviral agents
Lithium

8. 8
existing renal disease and age >65 years are the factors which increase its toxicity.
All the Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit prostaglandin
synthesis, leading to unopposed, intrarenal vasoconstriction. This decreases the
glomerular filtration rate. This results in fluid retention, with the risk of increasing
cardiac failure in patients with pre-existing cardiac dysfunction, and resistance to
antihypertensive therapy in patients with normal cardiac function.
Diuretics, particularly the more potent loop diuretics, for example, frusemide,
ethacrynic acid, bumetanide, may cause volume depletion. This decreases cardiac
output, particularly in patients who already have decreased ‘effective’ blood volume,
such as those suffering cardiac failure, liver failure or nephrotic syndrome. These
cause reduction in GFR by extracellular fluid volume contraction.
Analgesics are widely prescribed and can cause renal toxicity when used
acutely or chronically NSAIDs may impair glomerular filtration by inhibiting renal
vasodilator prostaglandins and cause acute renal failure. NSAID-induced
tubulointerstitial nephritis tends not to present with systemic findings of
hypersensitivity and is associated with proteinuria in the nephrotic range in most
cases. Paracetamol lacks peripheral prostaglandin inhibition, but may cause acute
tubular necrosis in overdose. Chronic interstitial nephritis and papillary necrosis can
develop as a consequence of long-term abuse of combination analgesics, particularly
those containing phenacetin.
By interfering with the production of angiotensin II, the ACE inhibitors
decrease efferent arteriolar regulation. Clinically significant alterations in renal
function may result, particularly in low perfusion states, such as renal artery stenosis
to a solitary kidney, or if there is bilateral renal artery disease. If the ACE inhibitor
adversely affects renal function you should consider the presence of functionally
significant renovascular disease, however the absence of such effect does not rule
out the presence of renal artery lesion. Furthermore, a small deterioration in renal
function may occur in patients who have no renovascular disease, but have a pre-
existing mild elevation of serum creatinine when they start an ACE inhibitor. This
deterioration will often reverse in time if the ACE inhibitor continued.
Drugs with negative inotropic effects, such as beta blockers and some
calcium channel antagonists, have the potential to impair renal function, especially if
cardiac output is already compromised. In clinical practice, the adverse effects on the
heart usually predominate so the drug is often stopped before the renal dysfunction
becomes clinically relevant.

9. 9
Vasodilator drugs, such as minoxidil and prazosin, rarely cause deterioration
of renal function themselves. However, they may be associated with marked salt and
water retention, requiring the addition of loop diuretics. Calcium channel blockers,
while causing oedema of the eyes and ankles, are actually natriuretic and do not
cause salt and water retention.
The kidney is exposed to many medications. Patients with comorbidities,
particularly the aged and those with pre-existing renal disease, diabetes and cardiac
failure, are especially at risk of renal impairment. With the increasing availability of
computer access to the relevant medical literature, it is wise to check the list of
precautions and adverse effects before prescribing for these patients.
C. Symptoms of drug-induced renal disease
Symptoms of nephrotoxic injury have a wide range and—in some cases—depend
uponthe type of toxin involved. In general, symptoms are
similartothoseofrenalfailureandinclude:
i) Urinary Signs
The kidneys help to flush out toxins through the urine, so when they are not
working properly, such as due to toxic kidney, certain urinary symptoms can be
present. According to Wrong Diagnosis, these include proteinuria and enzymuria.
Enzymuria is a condition in which there are enzymes present in the urine.
Proteinuria is a condition in which excessive amounts of protein are excreted in
the urine.
ii) Blood Signs
There are several different blood signs of toxic kidney. These include
increased blood-urea levels, increased levels of electrolytes in the blood,
increased blood-hydrogen ion level, increased blood pressure and anemia, says
Wrong Diagnosis. Anemia occurs when the number of red blood cells present in
the blood is reduced.
iii) Kidney Signs
Toxic kidney affects the kidney, so there are certain signs and symptoms
exclusive to the kidneys. According to Wrong Diagnosis, these include kidney
damage, tubular necrosis and kidney dysfunction. Kidney damage is simply
damage affecting the kidneys. Kidney dysfunction occurs when the kidneys are
not working at their optimal level. Tubular necrosis is a condition in which the
kidney's tubule cells become damaged due to the kidney tissues receiving less
oxygen than they need to function normally. Tubular necrosis ultimately leads to
acute kidney failure, according to Medline Plus, which can lead to decreased
urine output, fluid retention, nausea, drowsiness and confusion.

10. 10
iv) Imbalances and Fatigue
Water imbalance, electrolyte imbalance, and fatigue are also signs of toxic
kidney. These three signs occur as a result of the kidneys not functioning
properly. A water imbalance occurs when the body's sodium concentration is
either too low or too high, according to Discovery Health. When the amount of
water within the body either increases or decreases, an electrolyte imbalance can
occur. These imbalances can lead to muscle cramps, thirst, irritability, changes in
heart rate and blood pressure and seizures. Toxic kidney can also cause fatigue.
If the toxin's effect on the kidneys remains unchecked,more serious symptoms of
kidney failure may occur, including seizures and coma. You may have no
symptoms or warnings at all when the kidneys first begin to function improperly.
However, in some patients there may be earlier onset of symptoms.
D. Treatment
Treatment of nephrotoxic injury takes place in the hospital and focuses on
removing the toxin from the patient’s system, while maintaining kidney fuction.
Removal methods are targeted to specific toxins and may include the use of diuretics
or chelates to enhance excretion of the toxin in urine, or, in extreme cases, the direct
removal of toxins from the blood via hemodialysis or passing the blood over
unabsorbent substance such as charcoal. Support of kidney function depends on the
extent of damage to the organs and ranges from monitoring fluid levels to dialysis.
Most patients with ARF recover with conservative management which
includes fluid monitoring, protein restriction, drug adjustments, dietary or potassium
control, and dialysis (usually temporary).
E. Prevention
In brief, the best clinical approach to drug-induced nephrotoxicity is
prevention, which starts with the recognition that drug-induced renal injury occurs and
is seen predominantly in patients at risk. The following steps are necessary:
 Be aware of specific drugs.
 Identify patients at risk (those with renal insufficiency, dehydration, salt-
retaining states, diabetes, and multiplemyeloma).
 Be aware of increased risk in elderly patients.
 Whenever possible, select diagnostic procedures or therapeutic measures
without nephrotoxic potential.
 Avoid dehydration mandatorily in high-risk patients. Pretreatment hydration is
very important.
 Limit total daily dosage and duration of treatment with certain drugs.

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F. DRUG-INDUCED NEUROTOXICITY
Drug induced neurotoxicity is most often associated with the use of cancer
chemotherapeutic agents. In most cases, neurotoxicity manifests in the peripheral nerves,
but the central nervous system may be affected as well. Peripheral neuropathy has been
associated with vinca alkaloids (eg:vinchristine, vinblastine), taxanes (eg: paclitaxel) and
platinum compounds (eg: cisplatin). The neuropathy cause by vinca alkaloids and
taxanesis directly related to their primary mechanism of action, microtubule disruption. In
peripheral nerves, microtubule disruption is thought to result in altered axonal trafficking
and both sensory and motor neuropathy. Platinum-containing compounds may have
direct toxic effects on peripheral nerves.
VINCA ALKALOIDS
Example of drugs areVinchristine& Vinblastine. Vincristine itself is a vinca alkaloid
used to treat many cancers such as leukemia, lymphomas, sarcomas, and brain tumors.
Its main toxicityis an axonal neuropathy, resulting from disruption of the microtubules
within axons and interference with axonal transport. The neuropathy involves both
sensory and motor fibers, although small sensory fibers are especially affected. Virtually
all patients have some degree of neuropathy, which is the dose-limiting toxicity. The
clinical features resemble those of other axonal neuropathies such as diabetic
neuropathies. The followings are the symptoms to vinca-alkaloids-induced neurotoxicity:
 Paresthesias in the fingertips and feet and muscle cramps. These symptoms may
occur after several weeks of treatment, or even after the drug has been discontinued,
and progress for several months before improving. Children tend to recover more
quickly than adults.
 Loss of ankle jerks. Initially, objective sensory findings tend to be relatively minor
compared to the symptoms, but is common.
 Profound weakness, with bilateral foot and wrist drop and loss of all sensory
modalities.
 Severe neuropathies. This is likely to develop in older patients who are cachectic,
patients who have received prior radiation to the peripheral nerves or concomitant
hematopoietic colony-stimulating factors, and those who have preexisting neurologic
conditions such as Charcot-Marie-Tooth.
 Mild neuropathiescan receive full doses of vincristine, but when the neuropathies
increase in severity and interfere with neurologic function. Reduction in dose or
discontinuation of the drug may be necessary.
 Focal neuropathies.Although anecdotal reports indicate that glutamine may help
some patients with vincristine neuropathy, generally no effective treatment. Rarely,
vincristine can cause a fulminant neuropathy with severe quadriparesis that mimics
Guillain-Barré syndrome.

12. 12
 Autonomic neuropathy
 Abdominal pain and constipation.A paralytic ileus may occur because of the known
adverse gastrointestinal effects, patients receiving vincristine should take prophylactic
stool softeners and laxatives
 Impotence
 Postural hypotension
 Atonic bladders
 Cranial neuropathies
 The most common nerve to be involved is the oculomotor nerve, resulting in ptosis
and ophthalmoplegia. Other nerves that may be involved include the recurrent
laryngeal nerve, optic nerve, facial nerve, and the auditory vestibular system.
 Retinal damage and night blindness
 Jaw and parotid pain.
Central Nervous System (CNS) complications are rare, as vincristine poorly
penetrates the blood-brain barrier. Rarely, vincristine may cause the syndrome of
inappropriate secretion of antidiuretic hormone, resulting in hyponatremia, confusion, and
seizures. CNS complications unrelated to the syndrome of inappropriate secretion of
antidiuretic hormone may also occur. These include seizures, encephalopathy, reversible
posterior leukoencephalopathy, transient cortical blindness, ataxia, athetosis, and a
Parkinson syndrome.
The related vinca alkaloids vindesine and vinblastine tend to have less
neurotoxicity. This may be related to differences in lipid solubility, plasma clearance,
terminal half life, and sensitivities of axoplasmic transport. Vinblastine is now also used in
the treatment of non-Hodgkin lymphomas, mycosis fungoides, testicular carcinoma,
Kaposi sarcoma, and histiocytosis X.
 Management
The only effective management of vinca-induced neuropathy is reduction of the
dose, which usually reverses most major signs and symptoms without necessarily
requiring a discontinuation of the drug. Venlafaxine inhibits hyperalgesia in a rat model of
painful vincristine neuropathy. There is at least 1 case report of the successful utilization
of plasma exchange for vinblastine overdose with severe neuropathy as a feature;
however, this is an unusual circumstance.

13. 13
TAXANES
Taxanesare used to treat a variety of cancers including ovary, breast, and
nonsmall cell lung cancers. They contain a plant alkaloid that inhibits microtubule
function, leading to mitotic arrest. One of the examples of the drug is Paclitaxel.
Paclitaxel produces a dose-limiting peripheral neuropathy, which occurs in 60%
of patients receiving 250 mg/m2. Toxicity is predominantly characterized by a symmetric,
sensory axonal neuropathy affecting both large and small fibers. Symptoms usually begin
after 1 to 3 weeks of treatment. Patients develop:
1. Burning paresthesias of the hands and feet
2. Loss of reflexes
3. Neuropathy (often does not progress despite continued treatment, and there have
even been reports of patients improving with continuing therapy)
4. Arthralgias and myalgias(begins 2 to 3 days after a course of paclitaxel lasting 2 to 4
days)
5. Motor neuropathies that predominantly affect proximal muscles, perioral numbness,
and autonomic neuropathies.
6. Rarely causes visual scotomas, optic neuropathies, seizures, vocal cord palsies,
transient encephalopathies, or phantom limb pain in patients with prior amputation.
7. Acute encephalopathy and death.High-dose paclitaxel (greater than 600 mg/m2) can
cause this to patients between 7 and 23 days after treatment.
The neurotoxic effects of paclitaxel are increased when combined with cisplatin.
Liposomal encapsulation of paclitaxel may reduce the incidence of neurotoxicity. The
2014 American Society for Clinical Oncology Clinical Practice guideline on
chemotherapy-induced peripheral neuropathy does not recommend any agents for the
prevention of taxane-induced neuropathy but does provide moderate recommendation for
treatment of established neuropathy with paclitaxel.
Management/Prevention/Treatment of Paclitaxel-induced neurotoxicity may be found in
new formulations of paclitaxel to improve solubility and delivery, including nanoparticle
albumin-bound (Nab) paclitaxel and liposomal-encapsulated paclitaxel, may also assist in
enabling lower doses and reduced toxicity.

14. 14
PLATINUM COMPOUNDS
Example of platinum compounds drug is Cisplatin. It is an alkylating agent used
to treat ovarian, testicular, cervical, bladder, lung, gastrointestinal, and head and neck
cancers. It frequently causes neurotoxicity, especially peripheral neuropathies and
ototoxicity.
1) Neuropathy.
The main neurologic complication of cisplatin is an axonal neuropathy
affecting predominantly large myelinated sensory fibers.
Symptoms primarily result from injury to the dorsal root ganglion. The
peripheral nerve may also be affected. The neuropathy is characterized by subacute
development of numbness, paresthesias, and occasionally pain in the extremities.
Symptoms usually begin in the toes and then spread to the fingers and then, in
ascending fashion, affect the proximal legs and arms. Proprioception is impaired and
reflexes are lost, but pinprick sensation, temperature sensation, and power are often
spared. Nerve conduction studies show decreased amplitude of sensory action
potentials and prolonged sensory latencies consistent with a sensory axonopathy.
Sural nerve biopsy may show both demyelination and axonal loss.
The main differential diagnoses include paraneoplastic neuropathies and
neuropathies associated with autoimmune disorders such as Sjögren syndrome.
Paraneoplastic neuropathies tend to involve all sensory fibers and progress despite
discontinuation of cisplatin. Some patients test positive for antineuronal antibodies
(anti-Hu) in serum. Patients with autoimmune neuropathies often have clinical
features of the underlying connective tissue disease, and autoimmune antibodies are
usually present in the serum.
There is marked individual susceptibility to the development of cisplatin-
induced neuropathies. Typically, neuropathies develop in patients following
cumulative doses of cisplatin greater than 400 mg/m2. Increased dose intensity of
cisplatin administration does not appear to enhance the severity of the neuropathy.
Patients with mild neuropathies can continue to receive full doses of cisplatin. Once
the neuropathy becomes more severe and begins to interfere with neurologic
function, the clinician must decide whether to continue with therapy and risk
potentially disabling neurotoxicity, reduce the dose of drug, or discontinue the drug
and replace it with less neurotoxic agents. The most appropriate course of action
varies with each patient and must take into account factors such as the severity of the
neuropathy and the availability of less neurotoxic alternatives. After cessation of

15. 15
chemotherapy, the neuropathy usually continues to deteriorate for several months in
30% of patients. Most patients eventually improve, although recovery is often
incomplete. Many agents have been tested for the prevention or treatment of
chemotherapy-induced peripheral neuropathy, including neuropathy caused by
cisplatin.
2) Cranial neuropathies
Cisplatin may cause ototoxicity, leading to high-frequency sensorineural hearing
loss and tinnitus. The toxicity is due to peripheral receptor (hair) loss in the organ of
Corti and is related to dose. Audiometric hearing loss is present in 74% to 88% of
patients receiving cisplatin, and symptomatic hearing loss occurs in 16% to 20% of
patients. Cranial irradiation probably increases the likelihood of significant hearing
loss. The hearing loss tends to be worse in children, although they have a slightly
greater ability to improve after the drug has been stopped. Neurotrophin-4/5
enhances the survival of cultured spiral ganglion cells in vitro and may have
therapeutic value in preventing cisplatin-induced ototoxicity.
Cisplatin may also cause a vestibulopathy, resulting in ataxia and vertigo. It may
or may not be associated with hearing loss. Previous use of aminoglycosides may
exacerbate the vestibulopathy. Intraarterial infusion of cisplatin for head and neck
cancer produces cranial palsies in approximately 6% of patients. Intracarotid infusion
of cisplatin may also cause ocular toxicity, although these complications may also
rarely occur after intravenous administration of the drug. They include retinopathy,
papilledema, optic neuritis and disturbed color perception due to dysfunction of retinal
cones. Other complications of intraarterial cisplatin include headaches, confusion,
and seizures.
3) Myelotoxicity (Lhermitte sign).
This symptom, characterized by paresthesias in the upper back and extremities
with neck flexion, is seen in 20% to 40% of patients receiving cisplatin. Patients tend
to develop this symptom after several weeks or months of treatment. Neurologic
exam and MRI scans are usually normal and the Lhermitte sign usually resolves
spontaneously several months after the drug has been discontinued. It is thought to
result from transient demyelination of the posterior columns. Very rarely, a true
myelopathy has been reported.

16. 16
G. DRUG-INDUCED SKELETAL MUSCLE
Drug induced musculoskeletal disorders can potentially affect the spectrum of
anatomical structures including bone, connective tissue and the musculature. Skeletal
muscles represent a significant proportion of the body’s mass, receive a large fraction of
blood supply, and are metabolically highly active. This tissue therefore has significant
exposure to circulating drugs, which has the potential to cause drug induced disorders
ranging from trivial myalgias and asymptomatic elevations in creatine kinase through to
life threatening rhabdomyolysis with myoglobin induced renal failure.
A. Disorders
Myalgia (muscle pain) is characterised by diffuse muscle pain, tenderness and
cramps with the presence or absence of muscle weakness. Myalgia is not accompanied
by elevations in creatine kinase. While the presentation may be mild, symptoms such as
muscle cramps and aches or non-specific muscle pain may be a precursor to more
serious musculoskeletal conditions such as rhabdomyolysis.
Myositis is the inflammation of voluntary muscle fibres and has muscle symptoms
similar to myalgia but is accompanied by an elevation in serum creatine kinase (CK). The
two main sources of creatine kinase are myocardium (relatively small contributor) and
skeletal muscle which accounts for around 94% of creatine kinase. The presence of this
marker for muscle damage may result from exercise, physical muscle trauma, inherited or
acquired diseases or extrinsic drug causes.
Myopathy is a general term referring to any disease of muscles and is sometimes
used interchangeably with myositis. Myopathies can be acquired or inherited and can
occur at birth or in later life. There is a strong correlation between many drugs and
myopathy.
Features of drug induced myopathy are polymorphous and include:
 Fatigue
 Generalised muscle pain
 Muscle tenderness
 Muscle weakness
 Significantly elevated serum creatine kinase
(CK) > 10 x upper limit of normal (ULN)
 Nocturnal cramping
 Tendon pain
The symptoms of myopathy tend to be worse at night and are aggravated by
exercise. Myopathy should be considered when serum CK levels are more than 10 x
ULN, or in patients with increases in serum CK (less than 10 x ULN) accompanied by
symptoms of myalgia. Muscle biopsy is non-specific but may reveal muscle fibre
inflammation, atrophy and in some cases necrosis and regeneration. Muscle biopsy may
be useful where CK remains elevated post drug withdrawal.

17. 17
Rhabdomyolysis is a syndrome in which skeletal muscle disintegration results in
the release of large quantities of toxic muscle cell components into the plasma. The
etiology of skeletal muscle injury is quite diverse, including excessive muscular stress and
ischemia, genetic defects, and direct toxic or physical damage. In the past, the more
common causes of acute rhabdomyolysis were from crush injuries during wartime and
natural disasters.
More recently, as noted in one published series, drugs and alcohol have become
frequent causative agents in up to 81% of cases of rhabdomyolysis. Drug-induced
rhabdomyolysis can be divided into a primary or a secondary myotoxic effect. Primary
toxic-induced rhabdomyolysis is caused by a direct insult on the skeletal myocyte function
and integrity. Secondary effects of toxins are due to predisposing risk factors such as
local muscle compression in coma, prolonged seizures, trauma, and metabolic
abnormalities. The clinical features of rhabdomyolysis range from muscle weakness to
fulminant life-threatening acute renal failure. The classic triad of presenting symptoms is
skeletal muscle injury, pigmented urine, and some aspect of renal dysfunction. However,
in drug-induced rhabdomyolysis, a subclinical presentation without these common
features may be overlooked, due to other presenting symptoms that may predominate the
clinical findings.
B. Physiologic mechanisms of Rhabdomyolysis
Rhabdomyolysis is defined as a clinical and biochemical syndrome in which
leakage of intracellular myocyte contents are released into the extracellular fluid and
circulation. Myoglobin is a protein that functions as an important oxygen carrier that
maintains the ability of red muscles to consume oxygen.
The normal level of myoglobin in serum is 3 to 80 μg/L. The serum level of
myoglobin is dependent upon the glomerular filtration rate. When 100 g of muscle tissue
has been injured, the serum proteins reach the saturation level. All myoglobin above 230
mg/L is filtered through the glomerulus. The presence of myoglobin in the urine will
produce a dark red-brown pigmentation if the level exceeds 1g/L. At or below a pH of 5.6,
myoglobin dissociates into ferrihemate and globulin. Ferrihemate causes a direct
deterioration of renal function, impairment of renal tubular transport mechanisms, and cell
death.
Myoglobinuric renal failure may be explained by a direct nephrotoxicity due to
ferrihemate, tubular obstruction by precipitation of myoglobin casts, and alterations in
glomerular filtration rate. Myoglobin can be detected in the urine in levels as low as 5 to
10 mg/L with a dipstick method that uses the orthotolidine reaction. Hemoglobinuria may
also cause a positive orthotolidine reaction; however, the plasma will be pink, and red
blood cells will be present on the microscopic evaluation. Myoglobinuria may precede and

18. 18
resolve prior to an increase in creatine kinase (CK) due to a short half-life of 1to 3 hours.
Therefore, a negative orthotolidine reaction does not rule out rhabdomyolysis.
Human tissues are composed of three different CK isoenzymes. The predominant
isoenzyme is skeletal muscle and cardiac tissue is CK-MM. The function of CK is to
convert myocyte creatine phosphate into high energy phosphate groups (adenosine
triphosphate) used in energy requiring reactions. The release of CK into the serum may
reach levels up into the hundreds of thousands. Degradation of approximately 200 g of
muscle can cause an increase in serum CK. Therefore, total serum CK is the most
sensitive biochemical indicator of rhabdomyolysis. Serum concentration begins to
increase 2 to 12 hours after the initial muscle injury and will peak at 3 to 5 days. Thus it is
possible for myoglobinuria to be resolved prior to an elevated serum CK. Therefore, it is
important to remember that in the initial acute rhabdomyolysis syndrome, serum CK may
be normal.
When massive myocyte breakdown of cell membranes occurs, other intracellular
constituents are released besides myoglobin and CK. A substantial amount of fluid can
accumulate within the affected muscles causing elevated pressures in the fascial
compartments. Intracellular potassium is released that can cause a significant
hyperkalemia. Approximately 150 g of muscle necrosis will release more than 15 mmol of
potassium. The resulting hyperkalemia may increase the risk for cardiac arrhythmias and
complicate an existing acute renal failure. In the beginning phases of rhabdomyolysis,
calcium accumulates within the muscle with a resulting hypocalcemia. During the later
stages, calcium is mobilized from the necrotic muscle tissue and results in hypercalcemia.
Release of phosphate further contributes to the hypocalcemia by forming a calcium
phosphate product that is deposited in the muscle tissue. Other metabolic abnormalities
include metabolic acidosis, hyperuricemia, elevated lactate dehydrogenase, aldolase,
creatinine, uric acid, urea, and amino transferases.
C. Drug-induced toxic effects towards skeletal muscle
Drug-induced rhabdomyolysis can occur by a primary direct toxic effect on the
myocyte function or by an indirect secondary effect that predisposes the myocyte to
develop injury. There are more than 150 medications and toxins that have been
implicated as the etiology of skeletal muscle injury. Some of the proposed direct
mechanisms by which these medications alter myocyte function are inhibition of calcium
metabolism by the sarcoplasmic reticulum, impairment of the production of adenosine
triphosphate causing disruption of cell membranes, and alterations in carbohydrate
metabolism. The secondary mechanisms include drug-induced coma causing prolonged
immobilization and muscle compression, seizures, and myoclonus causing increased

19. 19
oxygen demands on skeletal muscle tissue. Trauma from drug-induced altered mental
status, agitation, and delirium can cause tissue ischemia and crush injury.
D. Drugs that cause rhabdomyolysis
 Acetaminophen
 Caffeine
 Hydrocarbons
 Methamphetamine
 Strychnine
 Amoxapine
 Carbone Monoxide
 Hydrocortisone
 Methanol
 Succinylcholine
 Amphetamines
 Chloral hydrate
 Hydroxyzine
 Mineralocorticoids
 Sympathomimetics
 Amphotericin B
 Chlorpromazine
 Inhalation anesthetics
 Morphine
 Theophylline
 Anticholinergics
 Cocaine
 Isoniazid
 Narcotics
 Trimethoprim-
sulfamethoxazole
 Antidepressants
 Dexamethasone
 Isopropyl Alcohol
 Neuroleptics
 Vasopressin
 Antihistamines
 Diazepam
 Ketamine Hydrochloride
 Phencyclidine
 Antipsychotics
 Diuretics
 Licorice
 Phenobarbital
 Baclofen
 Ecstasy
 Lithium
 Phenothiazines
 Barbiturates
 Ethanol
 Lorazepam
 Phenytoin
 Benzodiazepines
 Fluoroacetate
 Lysergic acid diethylamide
 Prednisone
 Betamethasone
 Glutethimide
 Loxapine
 Salicylate
 Butyrophenones
 Heroin
 Marijuana
 Serotonin antagonists
Many of the common drugs of abuse have been reported to cause
rhabdomyolysis. One report estimated that approximately 20% of all cases of
myoglobinuria due to rhabdomyolysis were the result of alcohol ingestion. Ethanol-
induced rhabdomyolysis may develop from direct toxic effects on the sarcoplasmic
reticulum by increasing sodium permeability and disrupting calcium homeostasis,

20. 20
disintegration of the cell membrane, and alterations in intracellular energy sources.
The secondary effects of alcohol pertain to the altered mental status, loss of
consciousness, and coma that can lead to prolonged immobilization and muscle
compression. Ethanol ingestions can present with a history of poor nutrition,
hypokalemia, and hypophosphatemia, which can predispose the patient to
rhabdomyolysis.
Cocaine, another common drug of abuse, can cause a direct effect on the
muscle tissue, inducing vasoconstriction and tissue ischemia. Cocaine has also been
shown to cause leakage of CK from skeletal muscle myocytes. Cocaine-associated
rhabdomyolysis may also be contributed to the state of hyperthermia and
hyperactivity, which increases energy requirements and depletes the energy
resources. When the body’s thermoregulatory mechanisms of heat production and
dissipation fail, the myocyte cannot maintain its function and is destroyed. There are
several other drugs that induce injury by this hypermetabolic mechanism, including
inhalation anesthetics, sympathomimetics, serotonin antagonists, antipsychotics, and
anticholinergics.
Ketamine hydrochloride is an analogue of phencyclidine and is used as a
dissociative anesthetic for procedural sedation. It can also be ingested, inhaled, or
injected as a drug of abuse. Ketamine hydrochloride, as well as phencyclidine, can
produce agitation and prolonged muscular activity that may contribute to muscle
damage. However, phencyclidine may be more likely to cause rhabdomyolysis due to
seizures, hyperthermia, and delirium requiring restraints that can predispose to
muscle tissue injury.
Methamphetamine, a drug of abuse and another stimulant, was implicated as
the most common cause of rhabdomyolysis. Ecstasy was also reported to cause
fulminant rhabdomyolysis. Ecstasy is 3,4-methylenedeoxymethamphetamine
(MDMA), which is an analog of amphetamine. One the most life-threatening
complications of Ecstasy overdose is hyperthermia. Ecstasy releases serotonin into
the brain, which stimulates sympathetic mechanisms to increase catecholamines.
Muscular hyperactivity and severe hyperthermia result from release of calcium from
the sarcoplasmic reticulum and increased metabolic demands. Other medications
that can cause prolonged muscular contractions such as choreoathetosis or dystonic
reactions are phenothiazines and butyrophenones. Prolonged seizure activity, which
can cause rhabdomyolysis, can be induced by isoniazid, strychnine, amoxapine,
loxapine, theophylline, lithium, and withdrawal from sedative hypnotics or ethanol.

21. 21
Caffeine is a common drug that is usually not implicated in acute ingestions
from overdose. Caffeine interferes with calcium transport by the sarcoplasmic
reticulum resulting in accumulation of calcium within the cell. This can potentiate
muscle contraction and increase the energy demands that may cause cell
destruction. Therefore, this patient’s rhabdomyolysis was most likely due to direct
toxic effects that caused increased muscular activity and myocyte injury.
Acetaminophen is a common agent used in pediatrics as an antipyretic and
an analgesic. It is well known that acetaminophen overdoses cause severe hepatic
injury, rhabdomyolysis, hypothermia, hyperglycemia, and acute renal failure.
Therefore, acetaminophen should be added to the list of drugs that cause direct toxic
effects on myocytes as well as hepatocytes.
Drugs that induce central nervous system depression can cause prolonged
immobilization, muscle compression, and tissue ischemia that results in myocyte
injury. Compounds such as narcotics, benzodiazepines, cyclic antidepressants,
antihistamines, ethanol, glutethimide, and barbiturates all cause an altered level of
consciousness and may predispose to the development of rhabdomyolysis. Carbon
monoxide poisoning may enable a patient unconscious for a prolonged period of time,
predisposing to the development of rhabdomyolysis. Carbon monoxide can cause a
functional anaemia that impedes oxygen delivery to tissues. Carbon monoxide also
impairs adenosine triphosphate production, causing a direct effect on myocyte energy
production. Other agents such as cyanide and hydrogen sulfide can inhibit electron
transport and disrupt adenosine triphosphate production.
There are many other drugs that induce rhabdomyolysis through other
mechanisms. Hypokalemia caused be diuretics, mineralocorticoids, licorice, and
amphotericin B can predispose to rhabdomyolysis. Corticosteroids appear to have a
direct toxic effect on skeletal muscle, as seen in severe asthmatics who develop
rhabdomyolysis. Acute hypersensitivity reactions producing rhabdomyolysis have
been reported with phenytoin and trimethoprim-sulfamethoxazole. Cholesterol-
lowering agents like HMG CoA reductase inhibitors have a direct effect on the
skeletal muscle tissue. Succinylcholine can cause myoglobinuria in the absence of
the hereditary disorder of malignant hyperthermia, especially in children.
Neuroleptic malignant syndrome is characterized by the gradual development
of hyperthermia, muscle rigidity, autonomic instability, altered mental status,
myoglobin, and elevated serum CK. Drugs that cause neuroleptic malignant
syndrome include phenothiazines, butyrophenones, antipsychotics, narcotics, and
antidepressants.

22. 22
Intrathecal baclofen infusion is used for children with cerebral palsy to treat
spasticity and dystonia. Multisystem organ failure and rhabdomyolysis developed
when the catheter became disconnected from the pump. The muscle injury that
caused the rhabdomyolysis may have been due to hypertonicity, prolonged seizures,
and hyperthermia.
E. Clinical presentations
Rhabdomyolysis may present with a wide variety of clinical symptoms from
mild myalgias to severe acute renal failure. Muscles may be tender, stiff, or weak.
However, most patients with drug-induced rhabdomyolysis do not complain of
swelling or tenderness over the involved muscle at the time of admission. They may
develop a “second wave phenomenon” in which a delayed increase in fascial
compartment pressure causes compression neuropathies, swelling, and tenderness.
Compartment syndromes in drug-induced rhabdomyolysis usually occur secondary to
prolonged immobilization or coma, which can result in contractures and amputations.
Treatment includes immediate surgical fasciotomy to release the increased
compartmental pressures. Acute renal failure is complicated by hypovolemia, cast
formation, renal vasoconstriction, and ferrihemate toxicity. Replacing circulating blood
volume and maintaining urine output is essential for prevention of acute tubular
necrosis. Disseminated intravascular coagulation can be significant in patients with
rhabdomyolysis. Thromboplastin and plasminogen activator are released from the
injured myocyte and cause fibrinolysis. Acute cardiomyopathy can present from direct
toxic effects of drugs on the cardiac muscle. Respiratory failure can result from
involvement of respiratory muscles during rhabdomyolysis.
F. Treatments
In any acute life-threatening ingestion or illness, the airway, ventilation, and
perfusion should be the initial priority. Thereafter, the goal of treatment of
rhabdomyolysis is to cease muscle destruction. The prevention of increased agitation,
seizures, and abnormal movements must be attempted with pharmacologic agents.
Treatment of hyperthermia is essential using external cooling measures and
controlling for muscular hyperactivity with benzodiazepines.
Electrolyte abnormalities that must be corrected are hyponatremia,
hypernatremia, hyperglycemia, hypocalcemia, and decreased phosphorous. If
compartment syndrome is present, the compartment pressures should be measured.
If compartmental pressures are over 30 to 50 mmHg, a fasciotomymust be
considered. Alkalinization of urine and mannitol has shown to be effective in some
patients with acute renal failure. In the case of drug-induced rhabdomyolysis,
eliminating the exposure of the toxic agent may be the only treatment.

23. 23
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